Nitric oxide as a key regulator of extracellular matrix modulation during ovarian follicle development
DOI:
https://doi.org/10.55184/ijpas.v78i02.569Keywords:
Nitric oxide, Extracellular matrix, Folliculogenesis, Ovulation, Matrix metalloproteinasesAbstract
Background: Extracellular matrix (ECM) remodeling is essential for maintaining the structural and functional integrity of ovarian follicles. The turnover of ECM is controlled by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Nitric oxide (NO), produced by follicular cells, contributes to follicular development and may influence ovarian ECM dynamics. The present study aims to determine the regulatory role of NO in the expression of ECM components during follicle development under an altered NO milieu. Methods: Adult female rats in the estrous phase were subjected to intrabursal injections of the nitric oxide synthase (NOS) inhibitor L-nitro-arginine methyl ester (L-NAME) or the NO donor sodium nitroprusside (SNP) to modulate in-vivo NO levels. Ovaries were collected at the subsequent estrous phase. Paraffin-embedded ovarian sections were stained with hematoxylin–eosin and Masson’s trichrome for histological and collagen analysis. ECM-related proteins, including MMP-9, TIMP-1, RECK, and SPARC, were analyzed using immunohistochemistry and Western blotting. Results: L-NAME–treated rats exhibited a significant reduction in the number of freshly formed corpora lutea and preovulatory follicles compared to the control group. Collagenase activity was reduced in L-NAME–treated ovaries, accompanied by increased collagen deposition, indicating impaired ECM remodeling. Furthermore, MMP-9 and SPARC expression levels were reduced, whereas TIMP-1 and RECK expression levels were elevated in NO-inhibited ovaries. Conclusion: These findings indicate that NO is an important regulator of ovarian ECM remodeling as it adjusts the proportion of MMPs to their inhibitors. NO signaling disruption changes the ECM dynamics, which may adversely affect folliculogenesis and luteal activity, influencing female reproductive health and fertility.
References
Budani MC, Tiboni GM. Novel Insights on the Role of Nitric Oxide in the Ovary: A Review of the Literature. Published online 2021. doi:10.3390/ijerph18030980
Luiking YC, Engelen MPKJ, Deutz NEP. REGULATION OF NITRIC OXIDE PRODUCTION IN HEALTH AND DISEASE. Curr Opin Clin Nutr Metab Care. 2010;13(1):97. doi:10.1097/MCO.0B013E328332F99D
Rosselli M, Keller R, Dubey R. Role of nitric oxide in the biology, physiology and pathophysiology of reproduction. Hum Reprod Update. 1998;4(1):3-24. doi:10.1093/humupd/4.1.3
Rostamzadeh A, Ahmadi R, Heydari M, Raoofi A. Effects of nitric oxide on reproductive organs and related physiological processes. Asian Pacific J Reprod. 2020;9(4):159. doi:10.4103/2305-0500.288583
Jablonka-Shariff A, Olson LM. The role of nitric oxide in oocyte meiotic maturation and ovulation: Meiotic abnormalities of endothelial nitric oxide synthase knock-out mouse oocytes. Endocrinology. 1998;139(6):2944-2954. doi:10.1210/endo.139.6.6054
Yamauchi J, Miyazaki T, Iwasaki S, et al. Effects of Nitric Oxide on Ovulation and Ovarian Steroidogenesis and Prostaglandin Production in the Rabbit*.; 1997. https://academic.oup.com/endo/article/138/9/3630/2987863
HIROSHI KATO YosmAKI A. Changes in Nitric Oxide Synthase Activity in the Gonadotropin Treated Rats: The Role of Nitric O during Ovulation Ovary Xide Of. Vol 46.; 1999.
Biswas S, Kabir SN, Pal AK. The role of nitric oxide in the process of implantation in rats. J Reprod Fertil. 1998;114(1):157-161. doi:10.1530/jrf.0.1140157
Curry J, Osteen KG. Cyclic Changes in the Matrix Metalloproteinase System in the Ovary and Uterus. Biol Reprod. 2001;64(5):1285-1296. doi:10.1095/BIOLREPROD64.5.1285
McCawley LJ, Matrisian LM. Matrix metalloproteinases: they’re not just for matrix anymore! Curr Opin Cell Biol. 2001;13(5):534-540. doi:10.1016/S0955-0674(00)00248-9
Curry TE, Osteen KG. The Matrix Metalloproteinase System: Changes, Regulation, and Impact throughout the Ovarian and Uterine Reproductive Cycle. Endocr Rev. 2003;24(4):428-465. doi:10.1210/ER.2002-0005
Nuttall RK, Sampieri CL, Pennington CJ, Gill SE, Schultz GA, Edwards DR. Expression analysis of the entire MMP and TIMP gene families during mouse tissue development. FEBS Lett. 2004;563(1-3):129-134. doi:10.1016/S0014-5793(04)00281-9
Yang WL, Godwin AK, Xu XX. Tumor necrosis factor-alpha-induced matrix proteolytic enzyme production and basement membrane remodeling by human ovarian surface epithelial cells: molecular basis linking ovulation and cancer risk. Cancer Res. 2004;64(4):1534-1540. Accessed June 17, 2019. http://www.ncbi.nlm.nih.gov/pubmed/14973065
Bagavandoss P. Differential distribution of gelatinases and tissue inhibitor of metalloproteinase-1 in the rat ovary. J Endocrinol. 1998;158(2):221-228. doi:10.1677/JOE.0.1580221
Hägglund AC, Ny A, Leonardsson G, Ny T. Regulation and localization of matrix metalloproteinases and tissue inhibitors of metalloproteinases in the mouse ovary during gonadotropin-induced ovulation. Endocrinology. 1999;140(9):4351-4358. doi:10.1210/ENDO.140.9.7002
Levin G, Maldonado Coelho T, Guimarães Nóbrega N, et al. Spatio-temporal expression profile of matrix metalloproteinase (Mmp) modulators Reck and Sparc during the rat ovarian dynamics. doi:10.1186/s12958-018-0422-2
Kennedy JL, Muse KN, Keeble SC, Curry TE. Hormonal regulation of tissue inhibitors of metalloproteinases during follicular development in the rat ovary. Endocrine. 1996;5(3):299-305. doi:10.1007/BF02739063
Ridnour LA, Windhausen AN, Isenberg JS, et al. Nitric oxide regulates matrix metalloproteinase-9 activity by guanylyl-cyclase-dependent and -independent pathways. Proc Natl Acad Sci U S A. 2007;104(43):16898-16903. doi:10.1073/pnas.0702761104
Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol. 2002;14(5):608-616. doi:10.1016/S0955-0674(02)00361-7
Brekken RA, Sage EH. SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol. 2001;19(8):816-827. doi:10.1016/s0945-053x(00)00133-5
Termine JD, Kleinman HK, Whitson SW, Conn KM, McGarvey ML, Martin GR. Osteonectin, a bone-specific protein linking mineral to collagen. Cell. 1981;26(1 Pt 1):99-105. doi:10.1016/0092-8674(81)90037-4
Bagavandoss P, Sage EH, Vernon RB. Secreted protein, acidic and rich in cysteine (SPARC) and thrombospondin in the developing follicle and corpus luteum of the rat. J Histochem Cytochem. 1998;46(9):1043-1049. doi:10.1177/002215549804600908/ASSET/IMAGES/LARGE/10.1177_002215549804600908-FIG5.JPEG
Podhajcer OL, Benedetti LG, Girotti MR, Prada F, Salvatierra E, Llera AS. The role of the matricellular protein SPARC in the dynamic interaction between the tumor and the host. Cancer Metastasis Rev. 2008;27(4):691-705. doi:10.1007/s10555-008-9146-7
Walpen S, Beck KF, Eberhardt W, et al. Downregulation of SPARC expression is mediated by nitric oxide in rat mesangial cells and during endotoxemia in the rat. J Am Soc Nephrol. 2000;11(3):468-476. doi:10.1681/ASN.V113468
Takahashi C, Sheng Z, Horan TP, et al. Regulation of matrix metalloproteinase-9 and inhibition of tumor invasion by the membrane-anchored glycoprotein RECK. Proc Natl Acad Sci U S A. 1998;95(22):13221-13226. doi:10.1073/pnas.95.22.13221
Oh J, Takahashi R, Kondo S, et al. The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell. 2001;107(6):789-800. doi:10.1016/S0092-8674(01)00597-9
Kerwin JF, Heller M. The argininenitric oxide pathway: A target for new drugs. Med Res Rev. 1994;14(1):23-74. doi:10.1002/med.2610140103
Shukovski L, Tsafriri A. The involvement of nitric oxide in the ovulatory process in the rat. Endocrinology. 1994;135(5):2287-2290. doi:10.1210/en.135.5.2287
Tsafriri A. Ovulation as a tissue remodelling process. Proteolysis and cumulus expansion. Adv Exp Med Biol. 1995;377:121-140. doi:10.1007/978-1-4899-0952-7_8
Luo Y, Zhu Y, Basang W, Wang X, Li C, Zhou X. Roles of Nitric Oxide in the Regulation of Reproduction: A Review. Front Endocrinol (Lausanne). 2021;12:752410. doi:10.3389/FENDO.2021.752410
Rostamzadeh A, Ahmadi R, Heydari M, Raoofi A. Effects of nitric oxide on reproductive organs and related physiological processes. Asian Pacific J Reprod. 2020;9(4):159-165. doi:10.4103/2305-0500.288583
Rosselli M, Imthurm B, Macas E, Keller PJ, Dubey RK. Circulating Nitrite/Nitrate Levels Increase with Follicular Development: Indirect Evidence for Estradiol-Mediated NO Release. Biochem Biophys Res Commun. 1994;202(3):1543-1552. doi:10.1006/BBRC.1994.2107
Jablonka-Shariff A, Ravi S, Beltsos AN, Murphy LL, Olson LM. Abnormal estrous cyclicity after disruption of endothelial and inducible nitric oxide synthase in mice. Biol Reprod. 1999;61(1):171-177. doi:10.1095/BIOLREPROD61.1.171,
Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N. Reactive oxygen species are indispensable in ovulation. Proc Natl Acad Sci. 2011;108(4):1462-1467. doi:10.1073/pnas.1017213108
Pinto CRF, Paccamonti DL, Eilts BE, Short CR, Godke RA. Effect of nitric oxide synthase inhabitors on ovulation in hCG-stimulated mares. Theriogenology. 2002;58(5):1017-1026. doi:10.1016/S0093-691X(02)00932-9
Hess KA, Waltz SE, Toney-Earley K, Degen SJF. The receptor tyrosine kinase Ron is expressed in the mouse ovary and regulates inducible nitric oxide synthase levels and ovulation. Fertil Steril. 2003;80(SUPPL. 2):747-754. doi:10.1016/S0015-0282(03)00774-X
Saed GM, Abu-Soud HM, Diamond MP. Inhibition of nitric oxide production by N-Nitro-L-arginine methyl ester increased the expression of type I collagen in human peritoneal fibroblasts. Fertil Steril. 2003;80:91. doi:10.1016/s0015-0282(03)02042-9
Gurjar M V., DeLeon J, Sharma R V., Bhalla RC. Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular smooth muscle cells. J Appl Physiol. 2001;91(3):1380-1386. doi:10.1152/JAPPL.2001.91.3.1380/ASSET/IMAGES/LARGE/DG0911004007.JPEG
Mutlag AM, Wang X, Yang Z, et al. Study on matrix metalloproteinase 1 and 2 gene expression and NO in dairy cows with ovarian cysts. Anim Reprod Sci. 2015;152:1-7. doi:10.1016/j.anireprosci.2014.11.006
Ishimaru RS, Leung K, Hong LS, LaPolt PS. Inhibitory effects of nitric oxide on estrogen production and cAMP levels in rat granulosa cell cultures. J Endocrinol. 2001;168(2):249-255. doi:10.1677/JOE.0.1680249
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